The primary objective of the proposed research is to compare the therapeutic efficacy of liposome-entrapped drugs and free drugs against several solid animal tumors, in particular lung metastasis of the B16 Melanoma and Lewis Lung Carcinoma and rat liver tumors. These types of model metastatic tumors more closely resemble the types of tumor normally relatively resistant to chemotherapy in the clinical situation. These studies will be carried out by using standardized liposome preparations varying with respect to biological half-life (by modification of composition) in order to vary rate of leakage of drug from the liposome and by varying liposome size (by different preparation methods) to alter the amount of liposomes trapped in the lungs and liver after intravenous injection. By combination of these factors we will be able to control and thereby optimize the rate of drug release in the target organ in order to maximize the therapeutic effects. These therapeutic studies will be made in conjunction with acute and chronic toxicity studies to determine therapeutic index and with target tumor and tissue and non-target tissue determinations of drug and active and inactive metabolites. The role of the reticuloendothelial system, in particular macrophages and macrophage-like cells in trapping, clearing and the chemotherapeutic effects of injected liposomes, will be studied by use of agents known to stimulate or depress cells of this system. The drugs we will use will be cyclophosphamide and adriamycin which have effects against solid tumors, and cytosine arabinoside which normally does not but may show effects where entrapped in liposomes. As studies have shown that liposomes act by a sustained release mechanism which protects drugs from rapid decrease or deactivation, we also will test other drugs in liposomes under a single dose schedule whose properties such as cell cycle stage specificity and/or short biological half-life necessitate multiple dose or infusion regimens when administered in the free state. An example of this type of drug is 5-fluorouracil.